Methods and compositions for treating inflammatory or autoimmune diseases or conditions using GRM8 activators

Abstract

The present invention provides methods for treating inflammatory or autoimmune disease using mGluR8 activators, such as mGluR8 activating antibodies, among others. The invention also features compositions containing mGluR8 activators, methods of diagnosing patients with mGluR8-associated inflammatory or autoimmune disease, and methods of predicting the response of an inflammatory or autoimmune disease or condition in a subject to treatment with mGluR8 activators.

What is claimed is: 
     
       1. A method comprising administering to a human subject in need thereof a small molecule mGluR8 agonist in an amount effective to reduce IL-8 secretion by macrophages, wherein IL-8 is elevated in the human subject, relative to a control. 
     
     
       2. The method of  claim 1 , wherein the human subject has an inflammatory disease or condition or an autoimmune disease or condition. 
     
     
       3. The method of  claim 1 , wherein the human subject has collagen-induced arthritis, coxsackie myocarditis, glomerulonephritis, pemphigus vulgaris, psoriasis, rheumatoid arthritis, uveitis, scleroderma, or dermatitis. 
     
     
       4. The method of  claim 3 , wherein the human subject has psoriasis. 
     
     
       5. The method of  claim 2 , wherein the human subject has inflammatory bowel disease, ulcerative colitis, Crohn's disease, or Hirschsprung's disease-associated enterocolitis. 
     
     
       6. The method of  claim 5 , wherein the human subject has inflammatory bowel disease. 
     
     
       7. The method of  claim 1 , wherein the small molecule mGluR8 agonist is an organic or inorganic compound having a molecular weight less than 5,000 grams per mole. 
     
     
       8. The method of  claim 1 , wherein the small molecule mGluR8 agonist is selected from CHEMBL192051, CHEMBL2381642, CHEMBL2381643, CHEMBL2381646, CHEMBL2381647, CHEMBL2381648, CHEMBL2381650, CHEMBL2381651, CHEMBL365368, CHEMBL2381640, CHEMBL2381641, CHEMBL2381644, CHEMBL2381645, CHEMBL2381649, CHEMBL2381652, CHEMBL218710, CHEMBL275079, CHEMBL375611, CHEMBL3616847, CHEMBL3804846, CHEMBL562551, CHEMBL229697, CHEMBL287703, CHEMBL34880, CHEMBL227288, CHEMBL277475, CHEMBL327783, CHEMBL330097, CHEMBL33567, CHEMBL39221, CHEMBL39338, CHEMBL40086, CHEMBL40123, CHEMBL66654, CHEMBL88553, CHEMBL88612, CHEMBL88999, (RS)-4-Phosphonophenylglycine, (S)-3,4-dicarboxyphenylglycine (DCPG), (RS)-3,4-DCPG, cyclobutylene APS, (R)-3,4-DCPG, O-Phospho-L-serine, VU 0422288, L-AP4, 1-Amino-1,3-dicarboxycyclopentane (ACPD), L-QA, (1S,3R,4S)-1-Aminocyclopentane-1,3,4-tricarboxylic acid (ACPT), and AZ12216052. 
     
     
       9. The method of  claim 1 , wherein the small molecule mGluR8 agonist is administered to the human subject in amount effective to reduce IL-8 secretion by macrophages by at least 10%, relative to a control. 
     
     
       10. The method of  claim 1 , wherein the small molecule mGluR8 agonist is administered to the human subject via a route selected from intravenous, intradermal, subcutaneous, percutaneous injection, oral, transdermal, and transmucosal. 
     
     
       11. The method of  claim 9 , wherein the small molecule mGluR8 agonist is administered to the human subject intravenously. 
     
     
       12. The method of  claim 1 , wherein the small molecule mGluR8 agonist is administered to the human subject locally via a route selected from epicutaneous, inhalational, intra-articular, intrathecal, intravaginal, intravitreal, intrauterine, intra-lesional, lymph node administration, intratumoral, and mucosal. 
     
     
       13. A method comprising administering to a human subject in need thereof a small molecule mGluR8 agonist in an amount effective to reduce IL-8 secretion by macrophages, wherein IL-8 is elevated in the human subject, relative to a control, and wherein the human subject has an intestinal inflammatory condition. 
     
     
       14. The method of  claim 13 , wherein the intestinal inflammatory condition is selected from inflammatory bowel disease, ulcerative colitis, Crohn's disease, and Hirschsprung's disease-associated enterocolitis. 
     
     
       15. The method of  claim 13 , wherein the small molecule mGluR8 agonist is an organic or inorganic compound having a molecular weight less than 5,000 grams per mole. 
     
     
       16. The method of  claim 13 , wherein the small molecule mGluR8 agonist is selected from CHEMBL192051, CHEMBL2381642, CHEMBL2381643, CHEMBL2381646, CHEMBL2381647, CHEMBL2381648, CHEMBL2381650, CHEMBL2381651, CHEMBL365368, CHEMBL2381640, CHEMBL2381641, CHEMBL2381644, CHEMBL2381645, CHEMBL2381649, CHEMBL2381652, CHEMBL218710, CHEMBL275079, CHEMBL375611, CHEMBL3616847, CHEMBL3804846, CHEMBL562551, CHEMBL229697, CHEMBL287703, CHEMBL34880, CHEMBL227288, CHEMBL277475, CHEMBL327783, CHEMBL330097, CHEMBL33567, CHEMBL39221, CHEMBL39338, CHEMBL40086, CHEMBL40123, CHEMBL66654, CHEMBL88553, CHEMBL88612, CHEMBL88999, (RS)-4-Phosphonophenylglycine, (S)-3,4-dicarboxyphenylglycine (DCPG), (RS)-3,4-DCPG, cyclobutylene APS, (R)-3,4-DCPG, O-Phospho-L-serine, VU 0422288, L-AP4, 1-Amino-1,3-dicarboxycyclopentane (ACPD), L-QA, (1S,3R,4S)-1-Aminocyclopentane-1,3,4-tricarboxylic acid (ACPT), and AZ12216052. 
     
     
       17. The method of  claim 13 , wherein the small molecule mGluR8 agonist is administered to the human subject in amount effective to reduce IL-8 secretion by macrophages by at least 10%, relative to a control. 
     
     
       18. The method of  claim 13 , wherein the small molecule mGluR8 agonist is administered to the human subject via a route selected from intravenous, intradermal, subcutaneous, percutaneous injection, oral, transdermal, and transmucosal. 
     
     
       19. The method of  claim 13 , wherein the small molecule mGluR8 agonist is administered to the human subject locally via a route selected from epicutaneous, inhalational, intra-articular, intrathecal, intravaginal, intravitreal, intrauterine, intra-lesional, lymph node administration, intratumoral, and mucosal. 
     
     
       20. A method comprising culturing human macrophages with a small molecule mGluR8 agonist and measuring IL-8 secreted by the human macrophages.